Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence.
Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence.
复制标题
p53和苹果酶的相互调节调节新陈代谢和衰老。
作者：
细胞衰老既能保护多细胞生物免受癌症的侵害，也有助于它们的衰老。卓越的肿瘤抑制因子p53在衰老的诱导和维持中起着重要作用，但p53如何执行这一功能仍然知之甚少。此外，虽然越来越多的证据支持代谢变化是许多细胞命运决定和p53介导的肿瘤抑制的基础，但代谢酶和衰老之间的联系很少。在这里，我们描述了一种新的机制，p53链接的功能。我们发现，p53抑制三羧酸循环（TCA循环）相关的苹果酸酶1（ME 1）和苹果酸酶2（ME 2）的表达。两种ME对NADPH产生、脂肪生成和谷氨酰胺代谢都很重要，其中ME 2具有更深远的影响。p53通过抑制MEs来调节细胞代谢和增殖。ME1和ME2的下调通过不同的Mdm 2和AMPK介导的机制以前馈方式激活p53，支持该途径并增强p53激活。ME1和ME2的下调也调节p53激活的结果，导致衰老的强烈诱导，但不是凋亡，而ME的强制表达抑制衰老。我们的研究结果定义了ME的生理功能，证明了维持p53激活的正反馈机制，并揭示了p53介导的代谢和衰老之间的联系。
Cellular senescence both protects multicellular organisms from cancer and contributes to their aging. The preeminent tumor suppressor p53 plays an important role in the induction and maintenance of senescence, but how p53 carries out this function remains poorly understood. Additionally, while increasing evidence supports the notion that metabolic changes underlie many cell fate decisions and p53-mediated tumor suppression, few connections between metabolic enzymes and senescence have been established. Here we describe a novel mechanism by which p53 links the functions. We show that p53 represses the expression of the tricarboxylic acid cycle (TCA cycle)-associated malic enzyme 1 (ME1) and malic enzyme 2 (ME2). Both MEs are important for NADPH production, lipogenesis, and glutamine metabolism, with ME2 having a more profound effect. Through inhibiting MEs, p53 regulates cell metabolism and proliferation. Down-regulation of ME1 and ME2 reciprocally activates p53 through distinct Mdm2 and AMPK-mediated mechanisms in a feed-forward manner, bolstering this pathway and enhancing p53 activation. Down-regulation of ME1 and ME2 also modulates the outcome of p53 activation leading to strong induction of senescence, but not apoptosis, while enforced expression of either ME suppresses senescence. Our findings define physiological functions of MEs, demonstrate a positive feedback mechanism that sustains p53 activation, and reveal a connection between metabolism and senescence mediated by p53.
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DOI：
10.1073/pnas.0610216104
发表时间：
2007-01-16
影响因子：
11.1
作者：
Blaettler, Sharon M.;Rencurel, Franck;Meyer, Urs A.
通讯作者：
Meyer, Urs A.
影响因子：
4.8
作者：
Guay, Claudiane;Madiraju, S. R. Murthy;Prentki, Marc
通讯作者：
Prentki, Marc
影响因子：
64.5
作者：
Godar S;Ince TA;Bell GW;Feldser D;Donaher JL;Bergh J;Liu A;Miu K;Watnick RS;Reinhardt F;McAllister SS;Jacks T;Weinberg RA
通讯作者：
Weinberg RA
影响因子：
5.8
作者：
Millard, Pierre;Letisse, Fabien;Portais, Jean-Charles
通讯作者：
Portais, Jean-Charles
DOI：
10.1073/pnas.0403954101
发表时间：
2004-07-13
影响因子：
11.1
作者：
Ventura, A;Meissner, A;Jacks, T
通讯作者：
Jacks, T